ES2283628T3 - MEDICINES SUPPLY DEVICE FOR TRANSPALPEBRAL IONTOPHORESIS. - Google Patents

Abstract

Device for ocular application of an active ingredient (1) comprising a main electrode (2) comprising an insulating layer (32), an adhesive layer (33) capable of linking the insulating layer to a conductive layer (34), presenting The main electrode is an area (21, 22, 23) suitable for contact with an eyelid of one eye.

Description

Drug delivery device by transpalpebral iontophoresis.

The present invention relates to some active substance delivery devices in particular by transpalpebral iontophoresis.

Iontophoresis uses electric current to allow the diffusion of an ionized molecule through a Biological membrane for therapeutic purposes. Under the effect of electric current, the permeability of the biological membrane is increased, allowing the passage of more important molecules in the sine of the cell, and the electric field pushes the molecules to Through this membrane. This technique has the advantage with regarding a classic topical application of increasing depth of penetration of the active substance proportionally to the intensity of the current used and at the time of application.

The current techniques of supply of active principles at eye level can be classified into five categories described as follows:

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route systemically (orally or intravenously), sometimes by bowling (discharge dose, short duration) does not give high concentrations in the eye (less than 1%) since the blood vessels of the retina and of other parts of the central nervous system are relatively impervious to numerous active ingredients. In addition, drugs used systemically may have side effects important about other organs of the body that the explicitly provided,

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the direct injections around the eye in periocular spaces or in the vitreous they are very traumatizing. In addition, after injection In the vitreous, the drug is rapidly diluted and disappear in some hours. This mode of administration presents certain risks as risks of infection, bleeding, cataracts or detached retina. These problems can be partially resolved by intraocular implants of scheduled release of active ingredients directly implanted in the vitreous, solid or semi-solid implants, sutured or not they need a surgical intervention for their implantation and a second intervention for the withdrawal of these material facts not biodegradable,

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the topical applications by drops only apply to a few principles assets that can be formulated in eye drops (solution or suspension) and they cannot treat the posterior segment of the eyeball since the penetration of the active substance is very limited and does not allow reach therapeutic concentrations beyond the segment anterior eyeball. Moreover, as tears wash the drug quickly, applications must be repeated frequently. It is possible to avoid these problems using a conjunctival insertion that allows a programmed release of active ingredients, increasing the contact time of the beginning active with the ocular surface. This solution presents the inconvenience of having a mediocre tolerance and a low benefit since high concentrations of active substance in the posterior segment of the eye (retina, nerve optical);

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the photodynamic therapy is a technique that involves injecting systemically an active principle and to activate them locally using a laser that has a certain wavelength. He main drawback of this therapy is that the patient must stay in the dark for several days, the active substance must be modified by the addition of agents, a photosensitive that blocks its activity until the laser is activated, the another that allows its fixation on biological compounds specific to the human body. This modification therefore supports that the active substance be fully tested pharmaceutically  before placing it on the market, even if it is a known medication. Finally the doctor must have a relatively expensive material in the acquisition of a laser specific;

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finally, there are some devices ocular iontophoresis as indicated in the patent US-A-6 154 671 describing a iontophoresis device whose deposit comprising the principle active comes into direct contact with the eyeball. A device of this type allows to obtain some concentrations and some intraocular residence times equal to or greater than techniques mentioned above being at the same time non-invasive. However, the technique presented in this document results from a Delicate use for long-term treatments and not can be used when the surface of the eyeball is affected.

In the field of regional anesthesia, apart from the general anesthesia necessary for long durations or for some non-collaborating patients, there are four techniques that refer to the eyeball:

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the topical anesthesia consists of topically instilling the anesthetic in the conjunctive cavities. This technique gives a short anesthetic. but enough for numerous operations, but less good quality, since there is more eye mobility, and causes increase in postoperative pain. It is frequent when the use of this technique takes place, make use of sedatives administered intravenously and that may cause complications such as respiratory arrest. In this case, the presence An anesthetist is fully recommended;

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the retrobulbar anesthesia involves injecting the anesthetic with the help of a needle in the back of the eyeball, in the interior of the space formed by the oculomotor muscles. This anesthesia technique presents risks of balloon perforation same eye, risks of retrobulbar hemorrhage, risks of optic nerve injuries, risks of cardiac or respiratory arrest, risks of accidental intravascular injection of the anesthetic as well as risks of retinal vascular occlusion. However, the quality and the duration of anesthesia is good,

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the peribulbar anesthesia involves injecting the anesthetic with the help of a needle of the eyeball and outside the space formed by the oculomotor muscles. This technique leads to them complications than before but less frequently since the penetration of the needle is less deep,

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finally, retrobulbar anesthesia by catheter is a technique that involves placing a catheter of the type peribulbar between (0.4 mm and 1 mm in diameter) with the help of a needle, within the retrobulbar or peribulbar space so that the anesthetic can be injected for long operations duration or administer it continuously even in postoperative. The risks caused by this anesthesia technique  They are identical to the previous two.

An objective of the present invention is provide an active substance delivery device eyepieces of a simpler job and able to target the areas Anatomical eye to be treated while being non-invasive.

For this purpose, according to the invention, an ocular application device of an active principle is provided comprising a main electrode comprising an insulating layer, an adhesive layer, capable of linking the insulating layer to a con- taining layer.
ductor, presenting the main electrode also an area suitable for contact with an eyelid of one eye.

Thus, the main electrode is placed directly on the eyelid of the eye to be treated. It allows like this  treat the area of the sclera that is more permeable and that presents less risk for vision (since there is no retina functional inside the eye around the cornea). For other part, the functional electrode does not come into direct contact with the eyeball. The device relies on the fact that the thickness of the skin at the level of the eyelid is the least important of the organism. Thus, the patient can use the device only without need the presence of the doctor, which is advantageous for some Long-lasting iontophoresis that should be performed (up to 18 h). This allows to treat some pathologies of the ocular annexes and of the glands of the eyelids. Abnormalities of the glands eyelids are responsible for abnormalities or decreased tear film quality, responsible for the pathologies of the eye surface

Advantageously, the application device eye of an active substance has at least one of the following features:

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he main electrode is generally oval,

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the Oval shape of the electrode has a larger outer diameter as maximum equal to approximately 40 mm and a smaller outside diameter maximum equal to approximately 35 mm,

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the zone presents a non-functional central zone surrounded by an area functional peripheral,

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the non-functional central zone is circular,

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the circular shape of the non-functional central zone has a diameter maximum equal to approximately 13 mm,

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the non-functional central zone is a hole that crosses the electrode,

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he main electrode is flexible,

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he main electrode also has an adhesive layer cutaneous,

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he main electrode also has a layer of foam linked to the conductive layer by a conductive adhesive layer,

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the foam layer is an absorbent layer suitable for performing the function deposit for the active substance,

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the insulating layer is a rigid helmet, and

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he Active ingredient is applied by iontophoresis.

An electrode is also provided according to the invention. comprising an insulating layer and an adhesive layer to bind the insulating layer to a conductive layer, characterized in that it has a non-functional central zone surrounded by a peripheral zone Functional suitable for coming into contact with an eyelid of the eye.

It is also provided, according to the invention, a ocular application procedure of an active substance that It includes some stages of placing a drug store of comprises a main electrode on the eyelids, of placement of a return electrode on adjacent tissues to the eyeball to be treated, penetrating through the eyelid of the active substance under the effect of an energy current that circulates between the electrodes.

Advantageously, the procedure has one of The following features:

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prior to placement of active electrode on the eyelids the active substance is arranged  under the eyelids,

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he main electrode has at least one of the characteristics cited,

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he active substance is topically (liquid, suspension, gel),

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he active substance is in the form of insertion.

Other features and advantages of the invention they will appear with the description of an embodiment and of variants. In the attached plans:

- Figure 1 is a schematic representation of an application device of an ocular active principle according to the invention,

- Figure 2 is a representation seen by on top of a main electrode according to the invention,

- Figure 3 is a schematic representation in section of the main electrode of figure 2,

- Figure 4 is a schematic representation in section of the main electrode of figure 2 according to a embodiment variant,

- Figures 5a and 5b are a representation of a first variant embodiment of an application device of an ocular active ingredient according to the invention,

- Figures 6a, 6b and 6c are a representation of a second variant embodiment of a device application of an ocular active principle according to the invention, and

- Figure 7 is a representation of a third variant embodiment of an application device of an ocular active principle according to the invention.

With reference to figure 1, the ocular application device of an active ingredient by iontophoresis according to the invention. The device 1 comprises a current generator 4 connected by a part to an electrode of return 3 and on the other hand to a main electrode 2.

The current generator 4 supplies a DC current between 0.5 mA and 5 mA preferably, even up to 10 mA, and this for a time between about 0.5 and about 30 min. preferably even up to about 18 hours. Depending on the resistance electrical of the tissues that form the circuit, resistance liable to evolve during iontophoresis, tension supplied by the generator is adapted according to Ohm's law, U = R.I, where U is the voltage in volts and R the total resistance of circuit in ohms and I the intensity chosen in amps. Without However the voltage supplied by this current generator does not may never exceed 80V. It may be planned to use a AC generator so as to avoid a pH increase under the effect of the rust-reduction phenomenon at electrode level, particularly in case of treatment dragged on. The frequency range of these currents is chosen at in order to allow a maximum increase in the permeability of the active tissue. In this particular case, the electrode return 3 must be electrocardiogram type and composed of a adhesive and by a low impedance Ag / AgCl film. Finally the generator can use a current profile that has about  very high voltage peaks, between 50 and 2500V approximately, in very short durations of the order of 0.01 to 0.1 seconds, and this, under low intensity (as described for the electroporation).

The possible to use other modes that allow improve the permeability of biological membranes: the magnetophoresis that uses magnetic fields, energy electromagnetic radio frequency and microwave, the ultrasonic energy Preferably, a device according to the invention uses iontophoresis or electroporation.

With reference to figure 2, the general form of the main electrode 2 is oval. Preferably, its diameter larger outside corresponds substantially to the larger diameter of the ocular orbit, that is approximately 40 mm. Likewise, its diameter smaller outside corresponds to the smaller diameter of the orbit, that is approximately 35 mm These dimensions correspond to the size running adult of the orbit. Other sizes and shapes can be provided according to the age and morphology of the patient a try.

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Electrode 2 has a non-functional zone 21 central. Preferably, this non-functional central area will be circular shape whose diameter corresponds substantially to the diameter of the cornea, that is approximately 13 mm. Preferably, the electrode has a through central hole that performs the non-functional zone function 21.

The functional peripheral zone surrounding the area Central non-functional presents two subzones 22 and 23. The subzone functional 22 is suitable to face the surface of the sclera located around the cornea. Also, the subzone Functional 23 is suitable for covering the surface of the eyelid where they place the hooks of the oculomotor muscles.

This particular form of the main electrode 2 allows, when the use takes place, to cover the maximum of surface of the sclera around the cornea and the maximum of surface of the eyelid where the hooks of the oculomotor muscles. It should be noted that the surface of the sclerotic around the cornea is the most permeable and it presents the least risk for vision since there is no retina in the inside of the eye around said cornea.

In general, the main electrode 2 is flexible. Thus, the main electrode 2 conforms to the eyelid when your placement takes place so that it fits the most intimately possible with the palpebral tissues and to allow, So, good electrical contact with the eyelid.

In another embodiment represented in the Figure 4, electrode 2 can be rigid. In this case, the same It comes in the form of a helmet 320 whose inner face is coated with a flexible 360 material suitable for absorbing anatomical differences, so that it fits most intimately possible with the palpebral tissues and thus allow good contact electric.

With reference to figure 3, the electrode structure They have been represented in it, in section, the six layers of material that can constitute the electrode, being some of these optional layers as will be seen. Each of these layers of material has a precise function.

The first layer 32 is an insulating layer. Is the part of the main electrode 2 that is fit to be in contact with the operator It allows the rest of the electrode to be isolated from the latter. This layer can be flexible and flat or rigid and helmet-shaped

Layer 33 is an adhesive layer that ensures the bonding function between the insulating layer 32 and a conductive layer 34 described below. Moreover, this adhesive layer 33 it allows to maintain on the conductive layer 34 an electrical cord 31 which connects the main electrode 2 to the generator 4.

Layer 34 is a conductive layer. This layer It is composed of a silver film and a film of carbon and its function is to distribute the electric current over the entire surface of the functional zone of the main electrode 2. The silver film of this conductive layer is located opposite the adhesive plate 33. It allows a good distribution of the current on the surface of the carbon film and ensures a contact optimal electrical with the electric cord 31. For its part, the carbon film is arranged in front of a layer of foam absorbent 36 described below. This carbon layer resists to oxidation in aqueous media under an electric current keep going. In more suitable material is a silver / carbon film of 0.2 mm thickness (Rexam conductive film reference 2252 by Rexam Image Products).

Layer 36 is an optional layer. It is a layer of absorbent foam suitable to be impregnated with the active substance or by a solution comprising an active ingredient before utilization. Therefore, this layer of absorbent foam should be very absorbent and understand pores of small dimensions of the order of 100 to 500 micrometers. The most suitable material is, by example, hydrophilic polyurethane foam with open cells of small density of the order of 0.05 to 0.1 g / cm3 (Hydrocrest ™ from Crest Foam Ind, Capu-cell® from TMP Technologies inc, Amrel® from Rynel, Medicell ™ Foam from Hydromer) This layer is optional according to the active substance be arranged in the foam before use or arranged directly under the eyelid before electrode placement on the eyelid

This absorbent foam layer 36 is bonded on the carbon film of the conductive layer 34 by a layer of conductive adhesive 35. This conductive adhesive should not be soluble in water

Finally, layer 37 is a layer of adhesive cutaneous. This layer is optional according to the main electrode Whether adhesive or not. The type of adhesive chosen should be conductive of the electric current on the one hand and should allow the passage of the active substance while adhering as little as possible to the skin so that it can be easily removed after utilization. This layer of skin adhesive can be located on the absorbent foam layer if it is present or directly on the carbon film of the conductive layer 3. 4.

One of the variants of embodiment consists of replace adhesive layers 33, conductive 34 and adhesive conductor 35 for a single layer of conductive adhesive (ARcare® 8881 of Adhesive Research Inc.) that advantageously meets all functions cited.

The first embodiment of the electrode main 2 is a flexible electrode comprising a layer of skin adhesive 37, a conductive layer 34, a layer of adhesive 33 and an insulating layer 32.

The second embodiment of the electrode main 2 is a flexible electrode comprising a layer of skin adhesive 37, a layer of absorbent foam 36, a layer of conductive adhesive 35, a conductive layer 34, a layer of adhesive 33 and an insulating layer 32.

The third embodiment of the electrode main 2 is a rigid helmet-shaped electrode comprising a layer of skin adhesive 37, a layer of foam 36 that performs the function of flexible material intended to absorb anatomical differences and to fit more intimately as possible with palpebral tissues when utilization takes place, a conductive adhesive layer 35, a conductive layer 34, a layer of adhesive 33 and a rigid insulating layer 32 forming the hull.

Finally, the fourth embodiment of the main electrode 2 is identical to the third embodiment described above, the foam layer being replaced by the absorbent foam layer 36.

The use of the electrode will now be described. and of its device according to the invention.

Within the framework of the first and third modes of realization of the main electrode 2, the operator, which can be a doctor or the patient himself, has the active substance or a solution comprising the active substance under the eyelid of the eye to be treated and then place the main electrode 2 on the eyelid and return electrode 3 on adjacent tissues of the globe Eye to treat. The electrodes are then connected to the generator and the circuit assembly is put under tension according to a defined intensity and a defined application time. TO Then the electrodes are removed.

In the case of the second and fourth modes of realization of the main electrode 2, the operator soaks the layer of absorbent foam with the active substance or a solution that Understand the active substance. Then position the electrode main on the eyelid of the eyeball to be treated and place the return electrode on the surrounding tissues of the globe Eye to treat. Then the operator performs the same operations than previously described.

The different medications or active ingredients suitable for administration by a device according to the invention They are the ones that need a regular application or over a long period. This is the case, for example, of corticosteroids, or nonsteroidal anti-inflammatory drugs (dexamethasone, methylprednisolone, hemisuccinate, etc ...) whose administration should be prolonged in very long periods in cases of chronic inflammation.

There are also antiallergics, neuroprotectors, neuromodulators, anti-glaucoma agents, antibiotics, antiangiogenic, neurotropic factors, anesthetics Numerous other molecules are under development. to stop even for the neurovascularization observed in the degenerative pathologies of the retina. Molecules can be transferred transclerally by iontophoresis or by injection vitreous and then iontophoresis. The iontophoresis device according to the invention simplifies the administration of these medications as previously seen.

Another indication of the application device of an active ingredient according to the invention refers to anesthesia local eyelid or oculomotor muscles located in the orbit, which are in number of six and that allow movements of rotation of the eye. It is the right internal muscle, the external right muscle, upper right muscle, muscle lower right, of the large oblique and the small oblique. To these, the eyelid lift muscle and orbicular muscle are added (may have interest for cosmetic surgery, treatment of exophthalmia or ptosis). This indication allows immobilization the eyelid and / or an aquinesia of the eye in the framework of operations of surgery

Other uses of the device ocular application of an active ingredient according to the invention is refer to the active ingredients that do not need an application recurring but cannot be managed by a device that has a direct corneal or scleral contact for a reason physiological, such as trauma to the surface of the eyeball or consequently in the sequelae of surgical order. Among the active ingredients concerned, the following can be mentioned antibiotics, antivirals, anti-inflammatories or antifungals for example.

Of course, many can be provided modifications to the invention without thereby leaving the framework of is.

For example:

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He return electrode 3 arranged on the tissues adjacent to the eyeball can be connected to the main electrode by of a non-conductive film 50 and arranged on the cheekbone of the patient to be treated as illustrated in figures 5a and 5b

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The main electrodes 2 can be in number of two (one for each eye) and arranged on a mask 100 (such as a mask at night used in air transport for example), the return electrode 3 associated with the generator (part 43) may be arranged on the patient's forehead preferentially, and connected to the main electrodes by means of the cords electrical 31, as illustrated in Figure 6a. Should Note that mask 100 is held over the head of the patient by elastic means such as a band.

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In a variant illustrated figure 6b of the arrangement above described, a return electrode and the generator (part 43) can be advantageously arranged inside the band elastic that holds the mask 100 comprising the two main electrodes 2 and this so that the electrode of return is on one of the cheekbones (or both in one layout variant where there would be two return electrodes). Here, the elastic support means also serves as a cord electric which is made in the form of conductive tracks by example.

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In the Figure 6c illustrates a pair of glasses 120 comprising two main electrodes 2 located in place and position of the glasses of the pair of glasses 120. A generator 4 is installed on the mount of the pair of glasses 120 and connected, on the one hand, to the two electrodes 2 and, on the other hand, to the return electrodes 30 which are preferably located under the main electrodes 2 so that they are in contact (while being isolated of these main electrodes) with the skins of the upper part of the patient's cheeks or located on the ends of the glasses of the pair of glasses 120 so that they are in contact with the skin behind the patient's ears.

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In the Figure 7 illustrates another embodiment variant in which the two main electrodes 2 are mounted on a bonnet 110 as well as part 43 comprising the generator and the electrode of return.

In the last four variants illustrated in Figures 6a, 6b, 6c, and 7, the return electrode may be arranged on the tissues of the face that surround the eyeball like the cheekbones, the forehead, the cheeks, etc ... so general. On the other hand, the generator may be associated with it. or not. It is possible, in some variants, to move the generator connected to the main electrodes 2 and return 3 by means of electrical wires Otherwise, the connection wires are integrated into the device in the form of conductive tracks by example.

These four embodiments are fine adapted to treat degenerative pathologies such as diabetic retinopathy, age-related macular degenerescence, retinitis pigmentosa Indeed, it is known, for these pathologies, that the probability that both eyes are affected It is high (in the order of 50% of cases). In this case, it is you need to treat both eyes at the same time or at the same interval of time alternately.

Claims (14)

1. Eye application device of a active ingredient (1) comprising a main electrode (2) that it comprises an insulating layer (32), a layer of adhesive (33) suitable to bind the insulating layer to a conductive layer (34), presenting the main electrode an area (21, 22, 23) suitable for entering contact with an eyelid of one eye. 2. Device according to claim 1, characterized in that the main electrode has a general oval shape. Device according to claim 2, characterized in that the oval shape has a larger outer diameter that is at most equal to approximately 40 mm and a smaller outer diameter that is equal to approximately 35 mm. Device according to one of claims 1 to 3, characterized in that the zone has a non-functional central zone (21) surrounded by a functional peripheral zone (22, 23). 5. Device according to claim 4, characterized in that the non-functional central zone is generally circular. 6. Device according to claim 5, characterized in that the non-functional central zone has a maximum diameter equal to approximately 13 mm. 7. Device according to one of claims 4 to 6, characterized in that the non-functional central zone is an orifice that crosses the main electrode. Device according to one of the preceding claims, characterized in that the main electrode also has a layer of skin adhesive (37). Device according to one of the preceding claims, characterized in that the main electrode also has a foam layer (36) linked to the conductive layer by a conductive adhesive layer (35). Device according to claim 9, characterized in that the foam layer (36) is an absorbent foam layer suitable for carrying out the function of deposit for the active ingredient. 11. Device according to one of the preceding claims, characterized in that the main electrode is flexible. 12. Device according to one of claims 1 to 10, characterized in that the insulating layer is a rigid helmet. 13. Device according to one of claims 1 to 12, characterized in that the active ingredient is applicable by iontophoresis. 14. Electrode for ocular application of a active ingredient comprising an insulating layer and an adhesive layer suitable for linking the insulating layer to a conductive layer (34), presenting this electrode an area suitable for contact with an eyelid